{"doi":"10.1016/j.jbc.2021.101174","title":"The Mitochondrial Ca2+ uniporter is a central regulator of interorganellar Ca2+ transfer and NFAT activation","abstract":"Mitochondrial Ca 2+ uptake tailors the strength of stimulation of plasma membrane phospholipase C-coupled receptors to that of cellular bioenergetics. However, how Ca 2+ uptake by the mitochondrial Ca 2+ uniporter (MCU) shapes receptorevoked interorganellar Ca 2+ signaling is unknown. Here, we used CRISPR/Cas9 gene knockout, subcellular Ca 2+ imaging, and mathematical modeling to show that MCU is a universal regulator of intracellular Ca 2+ signaling across mammalian cell types. MCU activity sustains cytosolic Ca 2+ signaling by preventing Ca 2+ -dependent inactivation of store-operated Ca 2+ release-activated Ca 2+ channels and by inhibiting Ca 2+ extrusion. Paradoxically, MCU knockout (MCU-KO) enhanced cytosolic Ca 2+ responses to store depletion. Physiological agonist stimulation in MCU-KO cells led to enhanced frequency of cytosolic Ca 2+ oscillations, endoplasmic reticulum Ca 2+ refilling, nuclear translocation of nuclear factor for activated T cells transcription factors, and cell proliferation, without altering inositol-1,4,5-trisphosphate receptor activity. Our data show that MCU has dual counterbalancing functions at the cytosol-mitochondria interface, whereby the cell-specific MCU-dependent cytosolic Ca 2+ clearance and buffering capacity of mitochondria reciprocally regulate interorganellar Ca 2+ transfer and nuclear factor for activated T cells nuclear translocation during receptor-evoked signaling. These findings highlight the critical dual function of the MCU not only in the acute Ca 2+ buffering by mitochondria but also in shaping endoplasmic reticulum and cytosolic Ca 2+ signals that regulate cellular transcription and function.","journal":"Journal of Biological Chemistry","year":2021,"id":154924,"datarank":0.62147020895873,"base_score":4.143134726391533,"endowment":4.143134726391533,"self_citation_contribution":0.62147020895873,"citation_network_contribution":0.0,"self_endowment_contribution":0.62147020895873,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":62,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9514,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":262127,"name":"Scott M. Emrich","orcid":"0000-0002-4804-7436","position":1,"is_corresponding":false},{"id":264986,"name":"Xuexin Zhang","orcid":null,"position":2,"is_corresponding":false},{"id":264987,"name":"Ping Xin","orcid":null,"position":3,"is_corresponding":false},{"id":542325,"name":"Vikas Arige","orcid":"0000-0002-0589-1880","position":4,"is_corresponding":false},{"id":656426,"name":"Trayambak Pathak","orcid":"0000-0002-0719-2995","position":5,"is_corresponding":false},{"id":656427,"name":"J. Cory Benson","orcid":"0000-0002-1446-9972","position":6,"is_corresponding":false},{"id":262128,"name":"Martin Johnson","orcid":"0000-0002-4706-8294","position":7,"is_corresponding":false},{"id":656428,"name":"Ahmed Emam Abdelnaby","orcid":"0000-0003-4775-3643","position":8,"is_corresponding":false},{"id":657570,"name":"Natalia Lakomski","orcid":null,"position":9,"is_corresponding":false},{"id":240809,"name":"Nadine Hempel","orcid":"0000-0002-5574-8783","position":10,"is_corresponding":false},{"id":473954,"name":"Jung Min Han","orcid":"0000-0002-2253-4156","position":11,"is_corresponding":false},{"id":657571,"name":"Geneviève Dupont","orcid":null,"position":12,"is_corresponding":false},{"id":147718,"name":"David I Yule","orcid":"0000-0002-6743-0668","position":13,"is_corresponding":false},{"id":262130,"name":"James Sneyd","orcid":"0000-0001-7305-2862","position":14,"is_corresponding":false},{"id":262132,"name":"Mohamed Trebak","orcid":"0000-0001-6759-864X","position":15,"is_corresponding":false},{"id":262126,"name":"Ryan E. Yoast","orcid":"0000-0002-7059-6829","position":0,"is_corresponding":true}],"reference_count":77,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:43:59.154159Z","pmid":"34499925","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}